Krüppel-Like-Factor 2, a new player in mucosal IgA homeostasis

Abstract Krüppel-Like-Factor 2 (KLF2) is a transcription factor that controls organ development, differentiation and trafficking of cells. In the immune system, KLF2 fosters the egress of T lymphocytes from the thymus via S1PR1 and promotes quiescent states of B lymphocytes as well as homing of antigen-specific IgG plasmablasts (PB) and plasma cells (PC) to the bone marrow (BM) via the α4β7 receptor. To investigate the PC-specific role of KLF2, we analyzed CD138+/TACI+ PB/PC subpopulations and isotype changes in various organs such as spleen (SP), BM, gut associated lymphoid tissues (GALT) and blood of KLF2-deficient mice in comparison to their mb1cre+ KLF2wt/wt controls. Therefore, FACS and Elispot analyses showed a striking reduction of IgA+ PB/PC in SP, BM and blood of non-immunized mice. Elisa and multiplex data revealed a strong reduction in serum IgA as well as (s)IgA in the feces of KLF2-deficient mice. However, frequencies of IgA+ PB/PC were not changed in GALT but total PB/PC accumulated in mesenteric lymph nodes (mLN) and Peyer’s Patches. In addition, IgA secretion of these cells was not effected. Based on these data, we conclude that the observed IgA-deficiency in KLF2-deficient mice can in part be explained by impaired egress of class switched PB/PC from their organ of generation to survival niches in the bone marrow and gut by controlling the expression of integrins. To address the consequences of a dysregulated PB/PC migration during infection, we are analyzing a GALT-dependent immunization with recombinant Flagellin which is known to trigger a systemic IgG as well as an mucosal IgA response. Furthermore, we are identifying KLF2 target genes that control PC egress and trafficking by RNAseq of IgA+ PB/PC from the mLN of KLF2-deficient mice.